The quinolonecarboxylic acid based antibacterial agents such as norfloxacin and ciprofloxacin, now used clinically, exhibit potent antibacterial activity. Efforts to synthesize or discover a quinolone based antibacterial compound exhibiting maximum antibacterial properties and minimum toxic side effects continue. Many investigators have focused their efforts on developing quinolones with aminoalkyl pyrrolidinyl moieties attached to the 7 position of the quinolone.
Within the chiral environment of living organisms, individual stereoisomers of biologically active compounds are often known to have unique properties relative to their related stereoisomers. In vitro and in vivo studies of quinolone derivatives with various aminoalkyl pyrrolidinyl 7 position side chains have shown that the activity of these compounds can be strongly influenced by the stereochemical positions of the atoms in the side chain. European Patent Application--Publication 0,443,498 A1, published Aug. 28, 1991, discloses an aminoalkyl pyrrolidinyl 7 position side chain quinolones having 2 asymmetric carbon atoms on a 3-amino-4-methylpyrrolidine ring attached to the 7 position of a quinolone. Two of the four possible stereochemical isomers were two to six times more active than the other two stereoisomers. U.S. Pat. No. 5,157,128, issued Oct. 20, 1992, (Hagen) describes the effect of stereospecific alkylation at the 1'-aminoethyl position of a 3-pyrrolidine substituent also substituted at the 7 position of a quinolone. Hagen reported that the R-(1,1-dialkylated-1-aminomethyl)pyrrolidine, when coupled at the 7 position of a quinolone leads to antibacterial agents with improved activity and safety.
This invention relates to a process for the synthesis of various optically active amino pyrrolidinyl stereoisomers, or enantiomers, that may be attached to quinolonecarboxylic acids or naphthyridones. The process disclosed by the procedures and examples herein allow the synthesis of these side chains in a more efficient manner than any previously disclosed method of synthesis. Novel intermediates are also disclosed.